The invention relates to compounds of the formula I 
in which
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94Nh2 which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group, 
R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
R3 is A, cycloalkyl, xe2x80x94[C(R6)2]nAr, xe2x80x94[C(R6)2]nxe2x80x94Oxe2x80x94Ar, xe2x80x94[C(R6)2]nHet or xe2x80x94C(R6)2xe2x95x90C(R6)2xe2x80x94Ar,
R6 is H, A or benzyl,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94C(R6)2xe2x80x94, xe2x80x94C(R6)2xe2x80x94C(R6)2xe2x80x94, xe2x80x94C(R6))2xe2x80x94COxe2x80x94, xe2x80x94C(R6)2xe2x80x94C(R6)2xe2x80x94COxe2x80x94, xe2x80x94C(R6)xe2x95x90C(R6)xe2x80x94COxe2x80x94, xe2x80x94NR6COxe2x80x94, xe2x80x94N{[C(R6)2]nxe2x80x94COOR6}xe2x80x94Oxe2x80x94 or xe2x80x94C(COOR6)R6xe2x80x94O(R6)2xe2x80x94COxe2x80x94,
Y is xe2x80x94C(R6)2xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94CONR6xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups can be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms can be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Het is a mono- or bicyclic saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different hetero atoms such as nitrogen, oxygen and sulphur and which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94OH2 and/or carbonyl oxygen,
Hal is F, Cl, Br or I,
n is 0, 1 or 2,
and salts thereof.
The invention also provides the optically active forms, the racemates, the diastereomers and the hydrates and solvates of these compounds.
The invention was based on the object of discovering novel compounds having valuable properties, in particular those which can be used for preparing medicaments.
It has been found that the compounds of the formula I and their salts have very useful pharmacological properties, coupled with good tolerability. In particular, they have factor Xa-inhibiting properties and can therefore be employed for combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and claudicatio intermittens.
Aromatic amidine derivatives having antithrombotic action are known, for example, from EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic disorders are described, for example, in WO 97/08165. Aromatic heterocycles having factor Xa-inhibiting activity are known, for example, from WO 96/10022.
The antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibiting action on the activated coagulation protease, known under the name factor Xa. Factor Xa is one of the proteases which is involved in the complex process of blood coagulation. Factor Xa catalyses the conversion of prothrombin into thrombin which in turn contributes to thrombus formation. An activation of thrombin can result in the occurrence of thromboembolic disorders. Inhibition of factor Xa can thus prevent thrombin formation. The compounds of the formula I according to the invention and their salts intervene in the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.
The inhibition of factor Xa by the compounds according to the invention and the measurement of the anti-coagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis 63, 220-223 (1990).
The inhibition of factor Xa can be determined, for example, by the method of T. Hara et al. in Thromb. Haemoscas. 71, 314-319 (1994).
The compounds of the formula I can be employed as medicaments in human and veterinary medicine, in particular for combating and preventing thromboembolic disorders such as thrombosis, myoca-dial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and claudicatio intermittens.
The invention provides the compounds of the formula I and their salts, and also a process for preparing compounds of the formula I according to Claim 1 and their salts, characterized in that
a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent, by
i) liberating an amidino group from its oxadiazole derivative by hydrogenolysis,
ii) replacing a conventional amino-protective group by treatment with a solvolysing or hydrogenolysing agent with hydrogen or liberating an amino group which is protected by a conventional protective group, or
b) that for preparing compounds of the formula I
in which
R1 is 
X is xe2x80x94COxe2x80x94 or xe2x80x94C(R )2xe2x80x94COxe2x80x94,
and R2, R3 and Y are as defined in Claim 1,
xe2x80x83a compound of the formula II 
in which
R3, R4, R5, W and Y are as defined in Claim 1,
xe2x80x83is reacted with a compound of the formula III 
in which
R1 is 
X is xe2x80x94COxe2x80x94 or xe2x80x94C(R6)2xe2x80x94COxe2x80x94,
R2 is as defined in Claim 1,
and L is Cl, Br, I or a free or a reactive functionally derivatized OH group, or
c) that for preparing compounds of the formula I
in which
R1 is 
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(R6)2xe2x80x94,
and R2 and X are as defined in Claim 1,
xe2x80x83a compound of the formula IV
Lxe2x80x94Yxe2x80x94R3xe2x80x83xe2x80x83IV
in which
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94xe2x80x94COxe2x80x94 or xe2x80x94C(R6)2xe2x80x94,
R3 is as defined in Claim 1, and L is Cl, Br, I or a free or a reactive functionally derivatized OH group,
xe2x80x83is reacted with a compound of the formula V 
in which
R1 is 
and R2 and X are as defined in Claim 1, or
d) that for preparing compounds of the formula I
in which
R1 is 
Y is xe2x80x94CONHxe2x80x94,
and R2 and X are as defined in Claim 1,
xe2x80x83a compound of the formula VI
R3xe2x80x94N=C=Oxe2x80x83xe2x80x83VI
in which
R3 is as defined in Claim 1,
xe2x80x83is reacted with a compound of the formula V 
in which
R1 is 
and R2 and X are as defined in Claim 1, or
e) that for preparing compounds of the formula I
in which
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2,
a cyano group is converted into an amidino group,
f) and/or that in a compound of the formula I, one or more radicals R1, R2 and/or R3 are converted into one or more radicals R1, R2 and/or R3 by, for example,
i) hydrolysing an ester group to give a carboxyl group,
ii) reducing a nitro group,
iii) acylating an amino group,
g) and/or converting a base or acid of the formula I into one of its salts.
For all the radicals which occur several times, such as, for example, R6, the meanings thereof are independent of one another.
Hereinabove and hereinbelow, the radicals or parameters L, X, Y, R1, R2 and R3 have the meanings given for the formulae I to VI, unless expressly stated otherwise.
In the above formulae, A is alkyl and has 1 to 20, preferably 1, 2, 3, 4. 5, 6, 7, 8, 9, 10, 11 or 12 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl. Alkyl is furthermore, for example, trifluoromethyl, pentafluoroethyl, allyl or crotyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl is in particular the radical of a bicyclic terpene, such as, for example, 3-menthyl; very particular preference is given to the camphor-10-yl radical.
COR6 is acyl and is preferably formyl, acetyl, propionyl, furthermore also butyryl, pentanoyl or hexanoyl.
Hal is preferably F, Cl or Br, but also I.
R2 is preferably H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ehylamino, diethyl-amino, acetamido, sulphonamido, methylsulphonamido, phenylsulphonamido, methylthio, ethylthio, methyl-sulphinyl, ethylsulphinyl, methylsulphonyl, ethyl-sulphonyl, phenylsulphinyl, phenylsulphonyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, furthermore also acyl or benzoyl.
R3 is preferably, for example, A, cycloalkyl, Ar, CH2Ar, CH2OAr, CH2CH2Ar, CH2Het, CH2CH2Het or CHxe2x95x90CH-Ar.
R6 is H, A or benzyl, but preferably H.
X is preferably, for example, absent, xe2x80x94COxe2x80x94, xe2x80x94OH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH=CHxe2x80x94COxe2x80x94, xe2x80x94NR6COxe2x80x94, xe2x80x94N{[CH2]nCOOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94.
Y is preferably, for example, xe2x80x94SO2xe2x80x94 or xe2x80x94COxe2x80x94, furthermore also xe2x80x94COOxe2x80x94, xe2x80x94CONHxe2x80x94 or xe2x80x94CH2xe2x80x94.
Ar is preferably unsubstituted phenyl or naphthyl, furthermore preferably naphthyl or phenyl which is mono-, di- or trisubstituted, for example by A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl, phenylsulphinyl, phenylsulphonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulphonamido, ethylsulphonamido, propylsulphonamido, butylsulphonamido, phenylsulphonamido, (4-methylphenyl)sulphonamido, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonyl-ethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, phenylaminocarbonyl, acyl or benzoyl, furthermore also biphenyl.
Ar is therefore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-acetamidophenyl, o-, m-or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylsulphonylphenyl, o-, m- or p-(phenyl-sulphonamido)phenyl, o-, m- or p-(methylsulphonamido)phenyl, o-, m- or p-methylthiophenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-, or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
Ar is very particularly preferably unsubstituted phenyl or naphthyl, furthermore preferably, for example, phenyl or naphthyl which is mono-, di- or trisubstituted by A, chlorine, methoxy, amino or dimethylamino, or is furthermore also biphenyl.
Arxe2x80x2 is in particular, for example, phenyl or naphthyl, furthermore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino)phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, nm- or p- (N,N-diethylamino)phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl or c-, m- or p-methylsulphonylphenyl.
Het is preferably, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-.imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, S-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo[(1,4]oxazinyl, furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl or dibenzofuranyl. The heterocyclic radicals may also be partially or fully hydrogenated. Het may also be, for example, 2,3-dihydro-2-, -3-, -4-or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-Furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -S-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3-or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo[1,4]oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or -6-yl, 2,3-(2-oxo-methylenedioxy)phenyl or else 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.
Het is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR , CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH . xe2x80x9cPolyxe2x80x9d means di, tri, tetra or penta.
The compounds of the formula I may have one or more chiral centres and may therefore be present in various stereoisomeric forms. The formula I embraces all of these forms.
Consequently, the invention provides in particular those compounds of the formula I in which at least one of the abovementioned radicals has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following moieties Ia to If which correspond to the formula I and where the radicals which are not defined more specifically have the meaning given for the formula I, but where
in Ia
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]n xe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group, 
R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
R3 is A, cycloalkyl, Ar, CH2Ar, CH2OAr, CH2CH2Ar, CH2Het, CH2CH2Het or CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N(CH2COOR6)xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Het is a mono- or bicyclic saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different hetero atoms such as nitrogen, oxygen and sulphur and which is unsubstituted or mono- or poly-substituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen,
Hal is r, Cl, Br or I and
n is 0, 1 or 2;
in Ib
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group, 
R2 is H,
R3 is A, cycloalkyl, Ar, xe2x80x94CH2Ar, xe2x80x94CH2OAr,
xe2x80x94CH2CH2Ar, xe2x80x94CH2Het, xe2x80x94CH2CH2Het or xe2x80x94CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH=CHxe2x80x94COxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N(CH2COOR6)xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, NH2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Het is a mono- or bicyclic saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different hetero atoms such as nitrogen, oxygen and sulphur and which is unsubstituted or mono- or poly-substituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen,
Hal is F, Cl, Br or I and
n is 0, 1 or 2;
in Ic
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group, 
R2 is H,
R3 is A, cycloalkyl, Ar, xe2x80x94CH2Ar, xe2x80x94CH2OAr, xe2x80x94CH2CH2Ar, xe2x80x94CH2Het, xe2x80x94CH2CH2Het or xe2x80x94CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH=CHxe2x80x94COxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N{CH2xe2x80x94COOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR )xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R5)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Het is a mono- or bicyclic heterocyclic ring system which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen selected from the group consisting of
thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole or benzothiophene,
Hal is F, Cl, Br or I and
n is 0, 1 or 2;
in Id
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group, 
R2 is H,
R3 is A, cycloalkyl, Ar, xe2x80x94CH2Ar, xe2x80x94CH2OAr, xe2x80x94CH2CH2Ar, xe2x80x94CH2Het, xe2x80x94CH2CH2Het or xe2x80x94CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N{CH2xe2x80x94COOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is phenyl,
Het is a mono- or bicyclic heterocyclic ring system which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen selected from the group consisting of
thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran,
Hal is F, Cl, Br or I and
n is 0, 1 or 2;
in Ie
R1 is xe2x80x94C(xe2x95x90NH,)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino-protective group, 
R2 is H,
R3 is A, cycloalkyl, Ar, CH2Ar, CH2OAr, CH2CH2Ar, CH2Het, CH2CH2Het or CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N{CH2xe2x80x94COOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR 6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is phenyl,
Het is a mono- or bicyclic heterocyclic ring system which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R6)2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen selected from the group consisting of
thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran,
Hal is F, Cl, Br or I and
n is 0, 1 or 2;
in If
R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NH2 which can also be monosubstituted by COOA, 
R2 is H,
R3 is A, cycloalkyl, Ar, xe2x80x94CH2Ar, xe2x80x94CH2OAr, xe2x80x94CH2CH2Ar, xe2x80x94CH2Het, xe2x80x94CH2CH2Het or xe2x80x94CHxe2x95x90CHxe2x80x94Ar,
R6 is H or A,
X is absent, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N{(CH2xe2x80x94COOR6}xe2x80x94COxe2x80x94 or xe2x80x94CH(COOR6)xe2x80x94CH2xe2x80x94COxe2x80x94,
Y is xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94,
A is alkyl having 1-20 C atoms in which one or two CH2 groups may be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms may be replaced by F,
Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nAr,
Arxe2x80x2 is phenyl,
Het is a mono- or bicyclic heterocyclic ring system which is unsubstituted or mono- or polysubstituted by Hal, A, Arxe2x80x2, COOR6, CN, N(R )2, NO2, Arxe2x80x94CONHxe2x80x94CH2 and/or carbonyl oxygen selected from the group consisting of
thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran,
Hal is F, Cl, Br or I and
n is 0, 1 or 2.
The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, such as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), and in particular under the reaction conditions which are known and suitable for the reactions mentioned. In these reactions, variants which are known per se and are not mentioned here in more detail can also be utilized.
If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by liberating the compounds of the formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting materials for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I but, instead of one or more free amino and/or hydroxyl groups, contain corresponding protected amino and/or hydroxyl groups, preferably those which, instead of an H atom which is bonded to an N atom, carry an amino-protective group, in particular those which, instead of an HN group, carry an Rxe2x80x2-N group, in which Rxe2x80x2 is an amino-protective group, and/or those which, instead of the H atom of a hydroxyl group, carry a hydroxyl-protective group, for example those which correspond to the formula I but, instead of a xe2x80x94COOH group, carry a group xe2x80x94COORxe2x80x3, in which Rxe2x80x3 is a hydroxyl-protective group.
Preferred starting materials also include the oxadiazole derivatives which can be converted into the corresponding amidino compounds.
The introduction of the oxadiazole group is effected, for example, by reacting the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformic ester, N,Nxe2x80x2-carbonyldiimidazole or acetic anhydride.
It is also possible for severalxe2x80x94identical or differentxe2x80x94protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups present differ from one another, in many cases they can be cleaved off selectively.
The term xe2x80x9camino-protective groupxe2x80x9d is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out at other sites of the molecule. Typical such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, those having 1-20, in particular 1-8 C atoms are preferred. The term xe2x80x9cacyl groupxe2x80x9d is to be interpreted in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulphonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and, above all, aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl or butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (xe2x80x9ccarbobenzoxyxe2x80x9d), 4-methoxybenzyloxycarbonyl, FMOC; arylsulphonyl such as Mtr. Preferred amino-protective groups are BOC and Mtr, and furthermore CBZ, Fmoc, benzyl and acetyl.
The term xe2x80x9chydroxyl-protective groupxe2x80x9d is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out at other sites of the molecule. Typical such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and furthermore also alkyl groups. The nature and the size of the hydroxyl-protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms are preferred. Examples of hydroxyl-protective groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulphonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
The liberation of the compounds of the formula I from their functional derivatives is effectedxe2x80x94depending on the protective group usedxe2x80x94for example with strong acids, expediently with TFA or perchloric acid, but also with other strong inorganic acids, such as hydrochloric acid or sulphuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulphonic acids, such as benzene- or p-toluenesulphonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are, preferably, organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, or furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are furthermore possible. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is used in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9:1. The reaction temperatures for the cleavage are expediently between about 0 and about 50xc2x0, and the reaction is preferably carried out at between 15 and 30xc2x0 (room temperature).
The groups BOC, OBut and Mtr can preferably be cleaved off, for example, with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30xc2x0, and the FMOC group can be cleaved off with an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30xc2x0.
Protective groups which can be removed by hydrogenolysis (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst, such as palladium, expediently on a support, such as carbon). Suitable solvents for this reaction are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100xc2x0 under pressures between about 1 and 200 bar, preferably at 20-30xc2x0 and 1-10 bar. Hydrogenolysis of the CBZ group is effected readily, for example, on 5-10% Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30xc2x0.
Compounds of the formula I
in which
R1 is 
X is xe2x80x94COxe2x80x94 or xe2x80x94C(R6)2xe2x80x94COxe2x80x94,
and R2, R3 and Y are as defined in Claim 1,
can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
In the compounds of the formula III, L is preferably Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulphonyloxy having 1-6 C atoms (preferably methylsulphonyloxy), or arylsulphonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulphonyloxy).
The reaction is generally carried out in an inert solvent, in the presence of an acid binder, preferably an alkali metal hydroxide, carbonate or bicarbonate or an alkaline earth metal hydroxide, carbonate or bicarbonate, or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or of an excess of the amine component of the formula II or of the alkylation derivative of the formula III may also be favourable. Depending on the conditions used, the reaction time is between several minutes and 14 days, the reaction temperature is between approximately 0xc2x0 and 150xc2x0, usually between 20xc2x0 and 130xc2x0.
Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetra-chloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitrites, such as acetonitrile; sulphoxides, such as dimethyl sulphoxide (DMSO); carbon disulphide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the solvents mentioned.
The starting materials of the formulae II and III are generally known. Those which are novel, however, can be prepared by methods known per se.
Compounds of the formula I
in which
R1 is 
Y is SO2, CO or COO,
and R2 and X are as defined in Claim 1,
can preferably be obtained by reacting compounds of the formula IV with compounds of the formula V.
In the compounds of the formula IV L is preferably Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulphonyloxy having 1-6 C atoms (preferably methylsulphonyloxy), or arylsulphonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulphonyloxy).
The reaction of the compounds of the formula IV with compounds of the formula V is preferably carried out in an inert solvent, with addition of a base and at temperatures as indicated above.
The starting materials of the formulae IV and V are generally known. Those which are novel, however, can be prepared by methods known per se.
Compounds of the formula I
in which
R1 is 
Y is CONH,
and R2 and X are as defined in Claim 1,
can preferably be obtained by reacting compounds of the formula VI with compounds of the formula V.
The reaction of the compounds of the formula VI with compounds of the formula V is preferably carried out in an inert solvent and at temperatures as indicated above.
The starting materials of the formula VI are generally known. Those which are novel, however, can be prepared by methods which are known per se.
Compounds of the formula I in which R1 is xe2x80x94C(xe2x95x90NH)xe2x80x94NF2 can furthermore be obtained from the corresponding cyano compound.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxamidine with hydrogen in the presence of a catalyst, such as, for example, Pd/C.
To prepare an amidine of he formula I (R1xe2x95x90xe2x80x94C(xe2x95x90NH)xe2x80x94NH2), ammonia can also be added onto a nitrile of the formula I (R1xe2x95x90CN). The addition is preferably carried out in several stages by a procedure in which, in a manner known per se, a) the nitrile is converted with H2S into a thioamide, which is converted with an alkylating agent, for example CH3I, into the corresponding S-alkyl-imidothioester, which in turn reacts with NF3 to give the amidine, b) the nitrile is converted with an alcohol, for example ethanol, in the presence of HCl into the corresponding imidoester, and this is treated with ammonia, or c) the nitrile is reacted with lithium bis(trimethylsilyl)amide and the product is then hydrolysed.
Furthermore, it is possible to convert a compound of the formula I into another compound of the formula I by converting one or more radicals R1, R2 R3 R4 and/or R5 into one or more radicals R11 R2, R3, R4 and/or R5, for example by reducing nitro groups (for example by hydrogenation over Raney nickel or Pd/carbon in an inert solvent, such as methanol or ethanol) to amino groups.
Esters can be hydrolysed, for example with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100xc2x0.
It is furthermore possible to acylate free amino groups in a customary manner with an acyl chloride or acid anhydride or to alkylate with an unsubstituted or substituted alkyl halide, expediently in an inert solvent, such as dichloromethane or THF, and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between xe2x88x9260 and +30xc2x0.
A base of the formula I can be converted into the associated acid addition salt with an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, and subsequent evaporation. Acids which give physiologically acceptable salts are particularly suitable for this reaction. Thus, it is possible to use inorganic acids, for example sulphuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulphaminic acid, or furthermore organic acids, in particular aliohatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulphonic or sulphuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulphonic acid, ethanedisulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, naphthalene-mono- or -disulphonic acids and lauryl-sulphuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for isolation and/or purification of the compounds of the formula I.
On the other hand, compounds of the formula I can be converted with bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal salts or into the corresponding ammonium salts.
Owing to their molecular structure, the compounds of the formula I according to the invention can be chiral and can consequently be present in various enantiomeric forms. They may therefore be present in racemic or in optically active form.
Since the pharmaceutical activity of the racemates and/or the stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates may be separated into enantiomeric compounds using chemical or physical means known to the person skilled in the art, or they may even be employed as such in the synthesis.
In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active separating agent. Suitable separating agents are, for example, optically active acids, such as the R- and S-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulphonylproline) or the various optically active camphorsulphonic acids. A chromatographic separation of the enantiomers can also be advantageously carried out with the aid of an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel). Solvents which are suitable for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example in the ratio 82:15:3.
The invention furthermore provides the use of the compounds of the formula I and/or their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by a non-chemical route. For this purpose, they can be brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid carrier or auxiliary, and if appropriate in combination with one or more further active compounds.
The invention furthermore provides pharmaceutical formulations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.
These formulations can be used as medicaments in human or veterinary medicine. Possible carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used, in particular, for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used for topical administration. The novel compounds can also be lyophilized and the resulting lyophilisates can be used, for example, for the preparation of injection formulations. The formulations mentioned can be sterilized and/or comprise auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs, flavourings and/or several further active compounds, for example one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be employed for combating and preventing thromboembolic disorders, such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and claudicatio intermittens. For this purpose, the substances according to the invention are usually preferably administered in dosages of between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on the most diverse factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, diet, on the administration time and route, and on the rate of excretion, medicament combination and severity of the particular disease to which the therapy applies. Oral administration is preferred.
All temperatures hereinabove and hereinbelow are given in xc2x0 C. In the following examples, xe2x80x9ccustomary work-upxe2x80x9d means: water is added, if necessary, the pH is brought to values of between 2 and 10, if necessary, depending on the structure of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulphate and evaporated and the residue is purified by chromatography over silica gel and/or crystallization. Rf values are for silica gel; mobile phase: ethyl acetate/methanol 9:1.
Mass spectrometry (MS):
EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+